Slow Inactivation in Human Cardiac Sodium Channels

Abstract

The available pool of sodium channels, and thus cell excitability, is regulated by both fast and slow inactivation. In cardiac tissue, the requirement for sustained firing of long-duration action potentials suggests that slow inactivation in cardiac sodium channels may differ from slow inactivation in skeletal muscle sodium channels. To test this hypothesis, we used the macropatch technique to characterize slow inactivation in human cardiac sodium channels heterologously expressed in Xenopus oocytes. Slow inactivation was isolated from fast inactivation kinetically (by selectively recovering channels from fast inactivation before measurement of slow inactivation) and structurally (by modification of fast inactivation by mutation of IFM1488QQQ). Time constants of slow inactivation in cardiac sodium channels were larger than previously reported for skeletal muscle sodium channels. In addition, steady-state slow inactivation was only 40% complete in cardiac sodium channels, compared to 80% in skeletal muscle channels. These results suggest that cardiac sodium channel slow inactivation is adapted for the sustained depolarizations found in normally functioning cardiac tissue. Complete slow inactivation in the fast inactivation modified IFM1488QQQ cardiac channel mutant suggests that this impairment of slow inactivation may result from an interaction between fast and slow inactivation.

C2C12 skeletal muscle cells adopt cardiac-like sodium current properties in a cardiac cell environment

“…Namely, these authors reported channel activation (36,45), as well as fast and slow inactivation (24,45), to occur at more hyperpolarized potentials in Na v 1.5 compared with Na v 1.4 channels. In addition, Na v 1.5 channels exhibited slowed kinetics of fast inactivation (24, 45), a reduced voltage dependence of slow inactivation (24), and a higher resistance to undergo slow inactivation (24,31). All these Na v 1.4-toNa v 1.5 shifts in Na ϩ current parameters were also found in our cardiac-conditioned compared with control cells (compare values in Tables 1 and 2).…”

“…To substantially improve cardiac contractility, the skeletal muscle graft should contract in synchrony with host cardiac tissue. This requires both electrical coupling between skeletal muscle cells and cardiomyocytes and cardiac ion channel function in skeletal muscle cells (31,35). Electrical coupling does occur in vitro (10,14,28) but has seriously been questioned in vivo (16,17,34).…”

“…Comparison of the Na ϩ current parameters in our control and cardiac-conditioned cells (Tables 1 and 2) with studies using heterologous expression systems to investigate functional differences between skeletal muscle Na v 1.4 and cardiac Na v 1.5 Na ϩ channels (24,31,36,45) suggests that cardiac conditioning generates more cardiac-like Na ϩ current properties. Namely, these authors reported channel activation (36,45), as well as fast and slow inactivation (24,45), to occur at more hyperpolarized potentials in Na v 1.5 compared with Na v 1.4 channels.…”

“…Namely, in the heart, longlasting (several hundred milliseconds) and repetitive (Ͼ1 Hz) depolarization is a normal characteristic of cardiomyocyte function. Under such conditions, skeletal muscle (Na v 1.4) Na ϩ channels [in contrast to cardiac (Na v 1.5) Na ϩ channels] would undergo almost complete slow inactivation within a few minutes (31,35). Consequently, the strong tendency of skeletal muscle Na ϩ channels to enter slow inactivation, and their tardy recovery thereof, would prevent repetitive firing of APs at rates Ͼ1 Hz (35) typical for the heart.…”

A Literature Review of the Use of Sodium Bicarbonate for the Treatment of QRS Widening

“…When channels undergo the structural change resulting in inactivation, no amount of electrical stimulus can open the channel, and this is known as the refractory period. Slow inactivation can occur over several seconds and may serve to regulate the excitability of the cell when it is undergoing repetitive depolarizations [27]. Fast inactivation is believed to occur through a Bhinged lid^mechanism from the loop located in between domains III and IVon the inside of the cell.…”